Glucocorticoids produced by the adrenal cortex exert many effects in the central nervous system ranging from spatial learning and cognition to stress and depression. Although high levels of glucocorticoids can be detrimental, in moderate concentrations, they can facilitate synaptic plasticity in the hippocampus and neuronal cell survival. The neuroprotective, anti-anxiety, and metabolic effects of glucocorticoids are carried out by the glucocorticoid receptor, which is abundantly expressed in the brain. Interestingly, the effects of glucocorticoids upon neuronal circuits are also strongly influenced by neurotrophins, such as Brain Derived Neurotrophic Factor (BDNF). However, the molecular mechanism of this regulation has not been explored. Recent evidence from our laboratories indicates there is bi-directional signaling between glucocorticoids and neurotrophins. For example, while BDNF signals through a Trk receptor tyrosine kinase, glucocorticoid receptor can bypass the need for BDNF and activate Trk signaling in neuronal cells (Jeanneteau et al PNAS 2008). In a reciprocal interaction, we have recently found that BDNF treatment promotes the phosphorylation of glucocorticoid receptor in neurons at several newly discovered sites. This proposal will dissect the biological consequences of BDNF-dependent phosphorylation of glucocorticoid receptor. Our hypothesis is that by altering phosphorylation, BDNF modulates glucocorticoid receptor gene regulatory functions, which in turn affects hippocampal-pituitary-adrenal (HPA) axis activity. These studies will begin to define the molecular mechanisms that affect feedback control and activity of the HPA system, and provide insight into how glucocorticoids and BDNF influence adaptive and maladaptive actions that are relevant to memory formation, stress response and depression.